Perenteral iron administration dramtically affects the normal metabolism of the essential trace element, zinc. Preliminary studies demonstrated a novel tissue specific induction by ion of the zinc binding protein, metallothionein (MT). Studies were developed to specifically examine the process(es) by which iron effects such changes. Much evidence indicates that metals such as Cd, Zn, Cu and Hg directly participate in the induction of MT via mRNA transcription. In contrast to iron, these metals bind to the newly synthesize polypeptide. In addition, the accumulation of inducing metal corresponds to a simultaneous accumulation of MT. The nature of iron accumulation in liver following parental iron administration does not similarly correspond. An increase in hepatic MT precedes any detectable change in the concentration of hepatic iron. Moreover, feeding studies involving diets high in iron produce markedly elevated hepatic iron but do not affect MT levels. An indirect hormonal component to iron induction of hepatic MT was proposed. Since adrenal corticoids and conditions of stress are well recognized as inducers of hepatic MT synthesis, this proposed mechanism appears tenable. The possible connection between metal and adrenal hormone involvement in MT induction has not been explored. The specific aims of the proposed work include: 1) to determine adrenal response of the animal following perenteral administration of iron, 2) to determine the effect of adrenalectomy on iron induced hepatic metallothionein accumulation, 3) to effect similar peripheral glucocorticoid fluctuations by adrenal tropic hormone and relate these changes to metallothionein synthesis and accumulation in liver, and 4) to determine the effect of zinc deficiency on iron and glucocorticoid induced zinc metallothionein accumulation. These studies will not only establish the nature of MT induction by iron but will further examine the biological role of adrenal hormones in the processes which regulate the synthesis of this unique zinc binding protein. They will also contribute knowledge in a broader sense, to the presently ill-understood biological role of metallothionein.